Lecture 2

Question 1

Advances

Answer 1

Some of the greatest advancements in neuroscience have arisen from advancements in technology. E.g. microscopy, staining technology, microdialysis, EEG, MRI, optogenetics. Advancements in engineering, computer science, physics. BRAIN initiative - new technologies, mathematics (needed to model neuron relationships).

Question 2

Spatial and temporal resolution

Answer 2

Tension between these two and invasiveness. Temporal - precision with which you can model/define a neuronal event in time. Spatial - precision with which you can localize the neuronal generator of a signal you’re measuring in the brain. Animals - can do patch clamp (good spatial and temporal), precise in specific neurons, can’t do in humans, have spatial scale of micrometers. Lesions and drug manipulations have relatively poor spatial and temporal resolution. Single-unit recordings in humans and animals are pretty good with both. On the good temporal resolution side but going to worse spatial - animal optical techniques, human intracranial ERPs, human optical, MEG, scalp ERPs.

Question 3

Analysis levels

Answer 3

Wilson - consilience. Reductionistic approach, then rebuild (consilience), bring it all together into a uniform whole. Social level of depression, organ/systems level fMRI structure and function, down to dendritic spines/neural wiring (cellular), neurotransmission at synaptic level, binding at molecular level.

Question 4

Lesion and brain perturbations

Answer 4

Traumatic brain injury, surgery, congenital disorders, degenerative disorders

Question 5

Phineas Gage

Answer 5

Brain injury: rod in brain, left orbitofrontal cortex (personality, salience of stimuli), became much less agreeable, people thought brain was involved in personality.

Question 6

S.M.

Answer 6

Congenital disorders: bilateral amygdala didn’t exist. No feeling of fear, understands the concept and can get a cortical representation of it. Psychopathy associated with low fear.

Question 7

H.M.

Answer 7

Surgery - terrible seizures, removal of the temporal lobe (many seizures originate there), took out hippocampus, couldn’t form new memories. Susan Corkin wrote a book about him, we learned lots about declarative memory formation, emotional/learning still intact though, dissociative process of memory, different systems serve different functions.

Question 8

Frontotemporal Dementia

Answer 8

Brain deteriorates, first become very happy b/c can’t ruminate, then destructive

Question 9

Cellular Structure and Biochemistry of Neural Tissue

Answer 9

Stains are mostly done in animals, 95% of medical research is on animals. Advances in engineering - microscopy. Electron microscope - electrons instead of light, can look into tissue, expensive, need dry tissue (complement to light microscopy).

Question 10

Visualizing Cellular Structures

Answer 10

Golgi stain: fill the whole cell including details like dendritic spines (where transmission and neuroplasticity happen, LTP), but they only stain a small portion of neurons. Good for seeing whole neuron in its entirety. This was the original staining but is still used. Early 1900s - Ramon y Cajal used golgi staining to better understand neurons and the nature of neural circuits. Neuron doctrine: neurons are distinct entities and information travels one way from dendrite to axon. Nissl stains - shows how many not anatomy, dye binds to RNA, RNA is near nucleus, cell bodies highlighted (not other parts), see distribution of cell bodies, counting number of cells or seeing distribution. Immunocytochemistry: can form antibodies for certain types of neurons, they bind to tissues, can see the neurons, more of the full neuron and can see contiguous neurons. It can detect proteins in tissue by capitalizing on the affinity of antibodies for specific proteins. Staining techniques provide different levels of analysis insights.

Question 11

Modern Staining

Answer 11

Lichman - Harvard. Brainbow - alters genome, actual cell expressing fluorescent protein that can be seen, can randomly distribute colors. Gives the precision of Golgi staining but can look at contiguous cells. Can see cell bodies and axons. Serial Electron Microscopy - reconstructs neuronal tissue with high spatial resolution. Uses electron microscope. These two types of viewing introduced connectomics: not examining things in isolation but pathways, human connectome project (NIH - understand connections in the brain, can do at different levels of analysis). Complex questions involve connectomics. Clarity: makes entire brain transparent and then images it with a light microscope. Limitation of most staining techniques are limited to a particular portion of tissue. You can label lots of molecules in whole brains with this. This isn’t really staining, but it is extracted tissue.

Question 12

Electrochemical Neural Activity

Answer 12

Staining looks at structure, this looks at electrical activity. Intracranial electrode recording: direct implantation of electrodes into the brain allows for both recordings and stimulation of single neurons or small groups of neurons. Great spatial and temporal resolution - you know what you’re reading from and recording activity in the moment. Goal of recording electricity. Stereotaxic apparatus: for precisely implanting electrodes into rodent or other brain. Electrode recordings provide direct readout of neural communication. Done in neurobiology, breakthroughs in visual system. This can be done in humans, invasive. Adolescents getting surgery to attenuate seizures but need to know where they’re happening: put electrodes in portion of the brain. Played games (reward stuff) while waiting for seizure - dopamine, anterior cingulate, ventral - strong dissociation in win vs lose, effect disappears as you go up, can see where in the brain you see win vs lose.

Question 13

EEG

Answer 13

Measures electrical activity of neurons non-invasively, through electrodes placed on the scalp. EEG has strong temporal (50-100ms) resolution but poor spatial. Worst spatial resolution probably. There’s an infinite number of sources a signal could come from (inverse problem). Can break down signal into distributions of frequencies. Awake = gamma, beta, high frequency (30-70cy/s). More synchronization when sleepy. Then dissociation into sleep architecture. EEG can index arousal and attentional engagement, sleep, seizure disorders. Can combine with MRI to get better spatial.

Question 14

ERP

Answer 14

Averaged EEG responses time-locked to discrete stimuli. Not just ambient EEG. More experimental, response to stimuli. Averaging across trials to get clear shapes and latency (time delay). Great temporal resolution, bad spatial just like EEG. These shapes and latencies index cognitive, emotional, and attentional responses to stimuli.

Question 15

Example ERP Study

Answer 15

Waiting longer for rewards associated with elevated SAT scores, educational attainment, better BMI, protection form mental illness and addiction (so we should care how the brain processes rewards). Modeling of ERP activity while waiting. Stronger outcome anticipation, more preferring of later reward. Preceding negatively predicts activation prior to reward, more deflection with more anticipation.

Question 16

Microdialysis

Answer 16

Measures the concentrations of chemicals (like neurotransmitters and hormones) in the extracellular fluid. Done live.

Question 17

Structural Neuroimaging

Answer 17

Structural MRI and DTI, examines structural anatomy of the brain in humans primarily

Question 18

Structural MRI

Answer 18

Generates “static” high-resolution images of tissue. Indexes distribution of hydrogen protons (water density covaries with tissue density - dense places have less water). Essentially a photo taken of the brain. Has magnets - radiofrequency pulsations. In a normal state, protons are spinning (Lamar frequency for each). Orientation of the spin is random. MRI aligns the spin orientation, creates a baseline from which you can measure variations. Then apply radiofrequency pulses at the particular spin degree (Lamar frequency) of the proton. This makes them all spin at 90 degree angle. When the pulse is removed, they go back to normal and release energy. the MRI picks up on this and generates the image. Importance? Evidence that schizophrenia is associated with neurodegenerative processes, biological marker of risk is increase in lateral ventricles (decrease in tissue, ventricles filled with cerebrospinal fluid).

Question 19

Diffusion Tensor Imaging

Answer 19

Also called diffusion weighted imaging. DTI is a MRI technique that generates images of the pathways of white matter tracts in the brain. DTI generates these images by assessing the mobility of water molecules along white matter tracts. Same technology as MRI, but studying connectivity, communicative pathways. Connectomics: examination of connective pathways in the brain. Can look at structural connections - tracts of white matter paths, indexing myelin sheath around axons. Axons vary quite a bit in length. Assessing mobility of hydrogen protons along the tracts. Isotropic molecules – lots of disorganization. Anisotropic – more detailed orientation of the movement of molecules. Along axon – water moves in an organized fashion across the axon. DTI are assessing how cohesively and smoothly water is moving in the brain, they move cohesively and smoothly along axons. Important for connectomics and also pathology (like multiple sclerosis – losing myelin around the axons, communication is less efficient). Used for basic science questions of connectivity or for medial purposes.

Question 20

Functional Neuroimaging

Answer 20

Structural generates static images of the brain. Function - researchers use functional neuroimaging (function and changes over time). fMRI and PET

Question 21

fMRI

Answer 21

When nerve cells are active, they increase consumption of energy which results in increased blood flow. fMRI indexes this distribution of blood flow to make inferences about the level of activation of neural tissue. fMRI – same scanner does MRI, fMRI, and DTI in same machine: gray part of image is structural MRI, but color part is a heat map of activity. Doing a task: relative to baseline or another task, heat map says whether something is more or less active. When nerve cells are activated, increase consumption of energy and glucose. Increase in energy corresponds to increase in blood flow. fMRI – indexing neuronal activation by measuring how much blood is going to that area of the brain. Not measuring electrical activity but the movement of blood - this is not a direct proxy of electrical activity though, so this is truly an inference about activity (although it has been demonstrated to be pretty valid). Increased local metabolic rate leads to increased blood flow in that region, that results in an increase in oxygenated hemoglobin (molecules that carry oxygen to a particular tissue), brain tries to get more blood than necessary, the more oxygenated hemoglobin (more fMRI signal). Indexing portion of oxygenated versus deoxygenated hemoglobin – this alters the magnetic signal in that area of the brain. Works well because the brain has a precise vascular system – there is increased blood flow to very small amounts of tissue (this gives us reasonable spatial resolution in the fMRI – but the vascular system thus limits the spatial resolution of fMRI). fMRI: useful for answering questions about activity – and what are the correlates of that activation as well. facial expressions: fear circuitry and reward circuitry, can do lab tasks in fMRI scanners with goggles.

Question 22

fMRI summary

Answer 22

local neuronal activity - increased metabolic rate - increased blood flow - increased oxygenated hemoglobin - uptake of oxygen less than supply - surplus oxygenated hemoglobin - decreased concentrations of deoxyhemoglobin - signal. Poor temporal resolution (3-10 seconds) because it indexes blood flow and not electrical activity. Few millimeters of spatial resolution (reasonable).

Question 23

Example fMRI study

Answer 23

Positive and neutral mood induction, looking at responses in reward task, nucleus accumbens. Depression also related to reduced neural responses to rewards – individuals who have depression have less activation in reward areas, biological markers of depression. Poor temporal resolution (ability to accurately assess the time course of brain activity) – blood is slow, arc of hemodynamic response is about 12 secs the best you can get is 2-4 seconds . Doesn’t pick up everything because blood is slow. Reasonable spatial resolution – better than EEG, you know within a few millimeters (but there are many neurons in each millimeter). Example: sex and aggression stimuli light up same areas of the brain – ventromedial hypothesis (but fMRI can only index a few millimeters of space, so it was actually different cells for each just in the same general area). Danger of false conclusions in fMRI, cells can do different things.

Question 24

PET

Answer 24

Can look at different types of molecules (blood, serotonin, other neurotransmitters - different molecules not just active or not). Inject radioactive isotope into blood of participant that binds to a particular molecule of interest. PET detects gamma rays as isotopes break down (decay at a set rate/half life). Where the isotopes break down is where the brain is active because they break down where they are being used. Combining it with fMRI can be useful. In a different scanner. Poor spatial and temporal resolution, primary advantage is it can look at different molecule types. Worse spatial than fMRI.

Question 25

Example PET

Answer 25

Chronic cocaine use downregulates the dopamine system (downregulates number of receptors as a protective mechanism). Healthy controls and addicts are given Ritalin/methylphenidate. Addicts have reduced activation in nucleus accumbens and ventral striatum. Conclusion is that you lose sensitivity and need more and more of the drug to get an effect.

Question 26

Neuromodulation

Answer 26

TMS, optogenetics

Question 27

TMS

Answer 27

non-invasively facilitate or disrupt processes in underlying cortical region. Can create a transient “legion” in human participants. Measure effect of TMS on behavior with behavioral and/or cognitive tasks during and after stimulation. - noninvasive way to make a “lesion” – changing small amount of the cortex (not very deep into the brain). Generator makes very powerful electrical pulse, the magnetic pulse modulates electrical activity in the brain. Can examine the effect on behavior. Used for memory a lot – ramping up or attenuating areas of the cortex. Magnetic fields induced by electromagnetic coils stimulate neurons of the underlying cortical surface.

Question 28

Optogenetics

Answer 28

Using tricks of gene therapy - insert photosensitive molecules into neurons (molecules can convert light into energy). Then shine light onto these neurons via fiberoptic cables implanted through the skull. Depending on the frequency of the light, can either excite or inhibit neurons. An advantage is that you have great precision over which cells are and are not modulated. Turning on and off cells in the brain. Comes from research on pond scum – have photosensitive molecules that convert light into electricity, can extract DNA of those molecules and inject them into tissue with retroviral technology, the tissue will grow photoreceptors. Use fiber optic cables to shine light on those molecules, can increase the firing rate or decrease it. Therapeutic applications: dopamine transmission into the substantia nigra to treat Parkinson’s. Dopamine transmission into the ventral striatum to treat depression. Amygdala responsivity in anxiety disorders and PTSD.

Question 29

Neuroimaging criticism

Answer 29

It still requires thought and critical thinking. Most of the criticism is on fMRI use. Neurocentrism/neuroseduction. Illusion that fMRI indexed activity is more causal or underlies psychological processes. Biological mediation versus causation. Lots of false positives and failures to replicate.

Question 30

Correlation and other things

Answer 30

Most correlations in neuroscience are between plus and minus .4. Correlation - relationship between two variables. Somatic manipulation - manipulating the brain affects behavior. Behavioral intervention - manipulating behavior/experience affects the brain.